Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies.

PURPOSE: To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants. METHODS: Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement. RESULTS: Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7-33-fold higher than the dISF concentrations. CONCLUSIONS: Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution.

Permeability and lipid organization of a novel psoriasis stratum corneum substitute.

Lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier properties. The main lipid classes are ceramides, cholesterol and free fatty acids. In previous studies a stratum corneum substitute (SCS) was developed, solely prepared from the SC lipids. The SCS mimics the lipid barrier properties of SC very closely. The present study aimed to design a psoriasis SCS (PS-SCS) mimicking several aspects of the lipid composition in SC from psoriasis patients. This PS-SCS showed a different lipid organization than SCS. The main differences were a reduced presence of an orthorhombic packing and an increased level of crystalline cholesterol. These changes resulted in lower flux of hydrocortisone across PS-SCS than across SCS and SC, which was most likely attributed to the higher level of phase separated crystalline cholesterol in PS-SCS. As propylene glycol (PG) is often used in dermatological formulations, in subsequent studies the interaction of PG with SC and SCS membranes was also investigated. These studies revealed that PG increased the permeability of hydrocortisone, mainly by selectively extracting cholesterol from SCS membranes and SC. This may play an important role in the penetration enhancing effect of PG.

Calcipotriol delivery into the skin with PEGylated liposomes.

The D-vitamin analogue calcipotriol is commonly used for topical treatment of psoriasis, but skin penetration is required for calcipotriol to reach its pharmacological target: the keratinocytes in the lower epidermis. Liposomes can enhance the delivery of drugs into the skin, but a major challenge for the development of dosage forms containing liposomes is to maintain the colloidal stability in the formulation. The purpose of this study was to investigate the effect of stabilising liposomes with the lipopolymer poly(ethylene glycol)-distearoylphosphoethanolamine (PEG-DSPE) on the physicochemical properties of the liposomes and the ability to deliver membrane-intercalated calcipotriol into the skin. Inclusion of 0.5, l and 5 mol% PEG-DSPE in the membrane enhanced the colloidal stability of the liposomes without compromising the delivery of calcipotriol from the vehicle into excised pig skin. Calcipotriol-loaded liposomes with 1 mol% PEG-DSPE did even provide for a significantly increased deposition of calcipotriol into the stratum corneum. The size of the liposomes affected the penetration of calcipotriol into the stratum corneum since small unilamellar vesicles enhanced calcipotriol penetration as compared to large multilamellar vesicles, indicating that the liposomes to some extent migrate as intact vesicles into the stratum corneum. However, calcipotriol penetrated the skin better than the lipid component of the liposomes, suggesting that at least a fraction of the drug is released from the liposomes during skin migration. In conclusion, PEGylation is therefore a promising approach for stabilising calcipotriol-containing liposomal dispersions without compromising their favourable skin accumulation properties.

Risk assessment of topically applied products.

The human risk of harmful substances in semisolid topical dosage forms applied topically to normal skin and broken skin, respectively, was assessed. Bisphenol A diglycidyl ether (BADGE) and three derivatives of BADGE previously quantified in aqueous cream and the UV filters 3-BC and 4-MBC were used as model compounds. Tolerable daily intake (TDI) values have been established for BADGE and derivatives. Endocrine disruption was chosen as endpoint for 3-BC and 4-MBC. Skin permeation of the model compounds was investigated in vitro using pig skin membranes. Tape stripping was applied to simulate broken skin associated with various skin disorders. BADGE and derivatives had a tendency to permeate pig skin membranes in vitro with higher fluxes in the tape stripped membranes compared to the non-treated membranes. Data from the in vitro skin permeation study and from the literature were used as input parameters for estimating the risk. The immediate human risk of BADGE and derivatives in topical dosage forms was found to be low. However, local treatment of broken skin may lead to higher exposure of BADGE and derivatives compared to application to normal skin. 3-BC permeated skin at higher flux than 4-MBC. Both UV filters are endocrine disrupting compounds with 3-BC being the more potent. UV filters in sunscreen are often present in high concentrations, which potentially may lead to high systemic exposure dosages. Thus, the risk associated with use of 3-BC and 4-MBC containing sunscreen with regards to endocrine disrupting effects was found to be high and more data is urgently needed in order to fully assess the human risk of 3-BC and 4-MBC in commercial sunscreen.